Integrins constitute a family of widespread heterodimeric cell surface adhesion receptors comprised of non-covalently associated alpha (α) and beta (β) subunits. To date, 18 different alpha subunits and 8 different beta subunits have been described in vertebrates, these forming 24 distinct heterodimers. Of these heterodimers, 12 contain the beta1 (β1, beta 1, beta-1, CD29) subunit.
To date, the precise structure of beta 1 integrin has not been identified. However, a prediction of the X-ray crystalline structure of beta 1 has been produced, and is shown in FIG. 17. The alpha and beta subunit of all integrins fold forming an extracellular headpiece which is connected to the membrane by a structure which can be likened to “2 supporting legs”, followed by a short transmembrane domain and cytoplasmic tail. The headpiece of the integrin heterodimer is composed of a beta propeller domain of the alpha subunit which closely interacts with the A domain of the beta subunit (the A domain also being known as the I-like domain of the beta subunit).
The affinity state of an integrin is regulated by the conformation of the headpiece. Rearrangement of the headpiece can be initiated by intrinsic ligands and by the binding of specific adaptors to the cytoplasmic domain.
The activation of beta 1 integrin is regulated in a cell-type dependent manner, and plays an important role in modulating cell functions. The avidity of an integrin is increased by the transition to an active conformational state. The specific conformational state of an integrin receptor can have a fundamental effect on integrin function. As such, in many instances, integrin conformation is more important than integrin expression levels when considering the physiological and pathological remodelling of tissue.
Integrin antagonists fall into three classes; direct inhibitors of ligand binding to the I domain of the alpha chain, allosteric inhibitors of the I domain of the alpha chain and allosteric antagonists of alpha chain/beta I-like domains (also known as the A domain).
Functional modification of beta1 integrin using antibodies is known. For example, International Patent Application Number WO 05/037313 discloses the use of compounds which modulate beta 1 integrin in order to mediate an increase in anabolism of the extracellular matrix. Such compounds are identified as being of use in tissue regeneration.
Further approaches to the modulation of beta 1 integrin functional activity focus on the modulation of beta1 integrin by means of activation or blocking of adhesion to a substrate under a defined set of conditions. Modulation of beta1 integrin in such a way has a number of limitations. Firstly, modulation is based on the understanding that integrins can exist in inactive, active and active and occupied states. Secondly, functional modulation was often achieved via different domains of the integrin. This may entail different downstream intracellular signalling, and therefore even if the effect on adhesion is similar, the functional end outcome can be different as each region appears to possess a different function. Further, beta1 integrin is known to exist in four different splice variants, with the resulting differences in the cytoplasmic domain implicating different downstream signalling.
Following extensive experimentation, the inventors have now surprisingly identified that compounds which interact with beta 1 integrin and function as antagonists of allosteric modulation have utility in tissue repair. The inventors have identified that such allosteric antagonists can function to promote tissue repair, this being characterised by the physical and/or mechanical restoration of damaged or diseased tissues through the growth of new cellular structures. Further, the inventors have further recognised that direct allosteric modulation of beta 1 integrin with a compound which functions as an allosteric antagonist can result in the reversal of functional and structural changes associated with tissue repair.